2-lower-alkylcortisone and 21-esters thereof



United States Patent E 2-LOWER-ALKYLCORTIS ONE AND "21- '"EESTERS THEREOF John A. Hogg and Frank H." Lincoln, Kalamazoo To'wn- "This invention relates to novel' steroidsg'more particularly to 2=lower-alkylcortisone and 2 l efsters thereof, and aproce'ss" for the production thereof. This application is a continuation-impart of our copending application 485,318, filed January "31, 1955.

' The "novel 2elower-alkylcortisone' and the 2l='esters thereof of the present"inventionunay'berepresented by p *the' following formula:

wherein R is hydrogen orithe acyl radical of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid containing from one totwelve carbon atoms, inclusive, and in which the lower-alkyl radical contains up to and including eight carbon atoms.

According to the present inventionfthetnovel 2-loweralkyl -.17oz hydroxy @21 acyloxy 4 pregnene"- 3,'1l,20-trioues(I) ofthetpresent invention areprepared .by the-oxidation 0131a 12 l-este'r. of -2-lower-alkylhydrocortisone, i.e., a 2 lower -:alkyl 1l)3,17c: 'dihydroxy -f 2'1'- acyloxy 4 -".pregnene-- 3,20 dione. Hydrolysis of a with, for example, aqueous sodium bicarbonate in &1 nitrogen. atmosphere, is productive 'of 2-methylcortisone, i.e.,

2 methyl 1704,21 dihydroxy 4 pregnene 3*,11i,20

1 trione.

2 methoxyoxalyl 1113,21 dihydroxy 4,17(20) 65 t [cis]-pregnadiene-3-one which is then reacted with methyl iodide to produce 2-methoxyoxyoxalyl-Z-methyl- 1 1fi,21-dihydroxy-4, 17 (20) 4 [cis] -p'regnadiene-3 -one. Reaction of 'this latter "compound with sodium f methoxide and methanol or aqueous *methanolic*sodium hydroxide a is 70 productive of 2 methyl 1113,21 dihydroxy 4,17(20)- ic is1-pregnadiene-3-one which, upon acetylation with 2,923,723 ipatented Feb. 2, 1960 2 -acetic--"anhyd'ride"- in "pyridine; converted to 2-mthyl- "1173 hydroxy 21' -acetoxy 4,l7(20) [cis] pregna- 'diene 3 -one*'which, in'turn, is converted by oxidative hydrox'ylation with osmium 'tetroxide' and hydrogen perox- 5 ide; or'osmium tetroxide and N-methylmorpholine oxide peroxide (prepared" by the reaction of 'N-methylrriorpholine with two rfiblar equivalents ot anhydrous hydro- 'gen peroxide in tert'iary bi ityl-alcohol) to Z-m'ethylll]3,17a 7 dihyclroxy '21- -acet'oxy -"4 pregnene 3,20 10 dione methyll lydrocortisone acetate). Hydrolysis of 'this 'c mpennd wnh aqueeus sodium bicarbonate "in methanol in a nitrogen atmosphere is productive of -2- ?-"riiethylhydrocoftisone -v'vl1'ich* c'an be reacylated with the "appropriate acid anhydride, 'acid chloride' or bromide, or add in the presence ofan esteiification catalyst, to produeaQl-"es fltherebt;etgyestersf acidssuch'as'specii p 2'l es'ter"of 2 methyldroeortisone; preferably is an =-'ester-'- of a hydrocarbon ear-Beanie acidcontainingfrom one to twelve carbon atoms, inclusive,-is productive'of-the-correspondingZlmtr of 2 inthylcortisone.

The" 'da't'ion process ot the present invention involves ther'eaction 'of al o'rganic carboxylicacid ester of 2- -loWer-alkylhydi'ocortisone, preferably a hydrocarbon 2 carboxylic =acid ester containing from one to twelve carbon atoms inclusive, with anoxidizingagent to produce the rre'sponding' '21-o'rga'nic carboxylic-'-"acid ester'of 2 new kyl'corti' sone, inwhichtheloWr-alkyl group contairi nip to arid 'inCIudifig eight carbGn atoms, as for example :rrietliyl, ethyl, propyl, isopr'opyl, butyl, hexyl,

, 'oc'tylar'id th'e' like.

Oxidizing agents which in'ay be used include 'the N- haloamides and N-haloimides wherein thehalogen has an atomic Weight from -3 5"to127, inclusive, e.g., N- ebromoaceta'inide, N-chloroacetamide, N-bromosuccinimide, Niodosuc ci-nimide,-- bromohydantoin, etc. preferably in tertiary butyl alcohol according to techniques known in =the-'art,-With-chromic acid or sodium dichromate in acetic acid, withtertiary-butyl hypochloride, etc. .fFhe-followingeXamp-les"areillustrative of the products and-processof the present invention but are not'tobe construed as limiting.

EXAMPLE 1 :2 methyl -17a hydroxy 21 --"acet0xy --4* pregnene- 3 ,1 1 ,20-1ri01'1e To'iawarm solutionof"2 0 0 milligrams of Z-methyl- 1118,1712: 'dihydroxy 21 aceto xy 4 pregnene 3,20 fdio'nelin'ten milliliters of tertiary butyl alcohol Was added, withstirring and in darkness, 0.l2 milliliter of pyridine renewed by 01154 gram of N-bromoacetarnide. The mixture Was stirred for 24 hours at room temperature and then mixed -With'fifty"milliliters of water containing about 1.5 grams of sodium sulfite. The tertiary butyl alcohol 'was- 'rernoved by distillation at reduced pressure and the 'residue maintained at four degrees centigrade for two hours. Thecrystalline precipitate was filtered, air dried and 'then "crystallized'from a mixture of five milliliters of ethyl acetate and five milliliters of Skellysolve B hexane hydrocarbons to give '150 milligrams of 2-methyl-17ahydroxy 21 acetoxy 4 wpregnene 3,11,20 -"trione melting at-205to 209 degrees Centigrade, having an [cab of 'p'lus 17O degrees in acetone and the analysis below.

Calculated for C H O C, 69.25;"I-I, 7.75. Found: (3,6894; H, 7.69.

Similarly, other Z-methyl 1113,17a dihydroxy-Zl-acyloxy-'4-pregnene-'3,20-diones are converted to other 2- methyl-l7a-hydroxy-21-acyloxy 4 pregnene-3,11,20-triones by oxidation of the llfi-hydroxy group, elg., with N-bromoacetamide, N-bromosuccinimide or N-chlorosuccinimide in tertiary butyl alcohol, chromic acid or sodium dichromate in acetic acid. Examples of Z-methyl- 17a-hydroxy-2l-acyloxy-4-pregnene-3,11,20 triones thus prepared include those wherein the acyl group is the acyl radical of, for example, a lower-aliphatic acid, e.g., formic, propionate, butyric, isobutyric, valeric, isovaleric, trimethylacetic, 2 -2methylbutyric, 3 -ethylbutyric, hexanoic, diethylacetic, triethylacetic, heptanoic, octanoic, a-ethyliso-valeric, a cyclic acid, e.g., 3fl-hydroxycholanic, 3fi-hydroxyetiocholanic, cyclopropylideneacetic, a cycloaliphatic acid, e.g., cyclopentylformic, cyclopentylacetic,

fl-cyclopentylpropionic, cyclohexylformic, cyclohexylacetic, fi-cyclohexylpropionic, an aryl or alkaryl acid, e.g., benzoic, 2, 3, or 4-methylbenzoic, 2,3- 2,4- 2,5- 2,6- 3,4- and 3,5-dimethylbenzoic, ethylbenzoic, 2,4,6-trimethylbenzoic, 2,4,6-trimethy1benzoic, a-naphthoic, 3- nethylnaphthoic, an aralkyl acid, e.g., phenylacetic,-,phenylpropionic, diphenylacetic, triphenylacetic, a dibasic acidv EXAMPLE 2 Z-ethyl-I 7a hydroxy-21-acetoxy-4-pregnene-3,I1,20-trione (A) 2-ETHYL113,17a-DIHYDROXY-21-ACETOXY-4- PREGNENE-3,20-DIONE The sodium enolate of 2-methoxyoxalyl-11,3,21-dihydroxy-4,17()-[cis]-pregnadiene-3-one, produced in accordance with S.N. 485,318, as previously described herein (i.e., by reaction of 11 3,2l-dihydroxy-4,17(20)- [cisJ-pregnadiene-3-one with dimethyl oxalate and sodium methoxide), is reacted with ethyl bromide to produce 2 methoxyoxalyl 2 4 ethyl 11,8,21 dihydroxy-4- l7(20)-[cis]-pregnadiene-3-one. The latter compound is reacted with sodium methoxide and methanol to produce 2 ethyl 11fl,21-dihydroxy-4,l7(20)-[cis] -pregnadiene-3-one. This is converted to the 21-acetate with acetic anhydride in pyridine and the acetate treated with osmium tetroxide and N-methylmorpholine oxide peroxide to produce 2-ethyl-11,6,17u-dihydroxy-21-acetoxy- 4-pregnene-3,20-dione.

(B) 2-ETHYL-17 a-HYDROXY-Z1-ACETOXY-4-PREGNENE- 3,11,20-TRIONE Proceeding exactly as in Example 1, above, Z-ethyl- 11B,17a-dihydroxy-21-acetoxy-4-pregnene 3,20 dione is reacted in tertiary butyl alcohol solution with N-bromoacetamide in the presence of pyridine. The product, 2-ethyl-17u-hydroxy-2l-acetoxy-4-pregnene 3,11,20 trione (2-ethylcortisone 21-acetate), is recovered, following the procedure of Example 1.

Other 2 lower alkyl-1 1 3,17a-dihydroxy-21-acetoxy-4- pregnene-3,20-diones are prepared by the procedure of A, above, substituting other alkyl halides for the ethyl bromide used therein, i.e., propyl iodide, isopropyl iodide, butyl bromide, hexyl iodide, and the like. And, following the procedure of B, above, these 2-lower-alkyl compounds are converted to the corresponding 2-lower-alkylcortisone 21-acetate.

H EXAMPLE 3 Z-methyl-I 70:,21-dihydroxy-4-pregnene-3,I1,20-trione A solution of 2-methyl-17a-hydroxy-21-acetoxy-4-preg- 'nene-3,11,20-trione in methanol was freed of oxygen gas by bubbling a stream of nitrogen therethrough. A 1.0 N solution of potassium bicarbonate was similarly freed of oxygen, and one molarproportion of the former mixed with about four molar proportions of the latter at a temperature between eighteen and ,twenty degrees centigrade and in a nitrogen atmosphere. The'mixture was stirred at room temperature for five hours, while protecting it from atmospheric oxygen with nitrogen. At the end of the period the solution was neutralized by the addition of a cold solution of glacial acetic acid and the thusformed Z-methyl 1711,21 dihydroxy-4- pregnene-3,11,20- trione recovered by evaporation and crystallization.

In the same manner, saponification of the 21-csters obtained, for example, by the procedure of Example 2, produces. 2-ethyleortisone and other 2-lower-alkylcortisones.

It is to be understood that the invention is not to be 1 limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. A compound selected from the group consisting of 2-lower-alkyl- 1701, 21-dihydroxy-4-pregnene-3 ,1 1,20-trione and 21-esters thereof represented by the following formula:

CHPO R wherein R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, and the lower-alkyl radical contains from one to. eight carbon atoms, inclusive.

2. Z-rnethyl 17a hydroxy 21 acyloxy 4 pregnene- 3,11,20trione wherein the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

v.3. Z-methyl 17a hydroxy 21 acetoxy 4 pregnene- 3 ,1 1,20-trione.

4. Compound represented by the following formula:

CHzOH- Fieser et al.: Natural Products Related to Phehanthrene, 3rd edition, pages 407, 423 (1949). 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 2-LOWER-ALKYL-17A,21-DIHYDROXY-4-PREGNENE-3,11,20-TRIONE AND 21-ESTERS THEREOF REPRESENTED BY THE FOLLOWING FORMULA: 